7. Project Summary/Abstract Current seasonal Influenza vaccines are proving to be ineffective, especially in at risk populations. For example, this year's inactivated flu vaccine had only a 9% efficacy rate against H3N2 infections in the elderly and the current live-attenuated Influenza vaccine (LAIV) is aged restricted for those above 49 years of age. Therefore there is glaring unmet need - seasonal Influenza vaccines that are effective. A translational, vaccine platform technology developed at Stony Brook University entitled SAVE (Synthetic Attenuated Virus Engineering) has shown initial success in yielding an anti-Influenza A vaccine in the laboratory strain A/Puerto Rico/8/34 that is effective in animals at very low doses. This SHIFT award seeks to transform this academic discovery into the beginnings of commercial product, by applying the SAVE technology to seasonally relevant human strains and then compare efficacy against the current LAIV. Demonstration of superiority will increase the commercial viability of the technology as well as fulfill a current unmet medical need - flu vaccines that have high efficacy in all populations. The drawbacks of current flu vaccines are two-fold- 1) both the inactivated injectable vaccine or the current LAIV require a large quantity of viral particles per dose >107, and 2) both have low efficacy in the aged population. The SAVE technology could provide a solution to both of these limitations. The SAVE platform relies on synthetic biology and the re-designing of a target virus's entire genome to yield a vaccine strain. This customization process uses software- based algorithms to 're-code' the genome of a target virus. Genomic 're-coding' results in a virus that is antigenically identical (i.e. looks exactly like the wild-type, virulent strain) but possesses a genome with hundreds of mutations rendering it attenuated in the host. Since proteins of the SAVE-designed vaccine strain are one hundred percent identical to the virulent strain, animals vaccinated with SAVE-designed vaccines develop a robust and protective immune response. SAVE is a platform technology that has had preliminary success constructing vaccine candidates for multiple, unrelated target viruses including poliovirus and Influenza a virus (Science 2008, Nature Biotech 2010). In Phase I of this proposal we will apply the SAVE technology to construct vaccine candidates for seasonal influenza strains that are clinically relevant and subsequently we will compare these strains to the current commercial live-attenuated influenza vaccine to demonstrate commercial viability. In Phase II we will build upon our success and test our SAVE-designed seasonal influenza vaccine candidates in a ferret model.